Aziridines, the triangular, comparably highly-strained nitrogen analogues of epoxides, are important synthetic intermediates (i.e., building blocks) en route to structurally complex molecules because of their versatility in myriad regio- and stereo-selective transformations (ring openings and expansions as well as rearrangements). The aziridine structural motif, predominantly N—H and to a lesser extent N-alkyl, and N-aralkyl, also appears in biologically active natural products (e.g., azinomycins and mitomycins). As a result, the synthesis and chemistry of aziridines has been the subject of intense research during the past 25 years, resulting in multiple aziridination methods. Most of these methods rely either on the transfer of substituted nitrenes, which are generated using strong external oxidants, to the C═C bond of olefins or the transfer of substituted carbenes to the C═N bond of imines (see Scheme A). Normally, the result is an aziridine bearing a strongly electron-withdrawing N-protecting group (e.g., Ts: para-toluenesulfonyl, Ns: para-nitrophenylsulfonyl); removal of these N-sulfonyl protecting groups is problematic as it often results in the undesired opening of the aziridine ring. In addition, the high reactivity of N-protected nitrenes might give rise to non-productive allylic C—H amination products, as well as the loss of stereospecificity. Clearly, the direct synthesis of N—H (i.e., N-unprotected), N-alkyl, and N-aralkyl aziridines would alleviate the above problems. However, a practical, functional group-tolerant and environmentally benign direct preparation of N—H), N-alkyl, and N-aralkyl aziridines from structurally diverse olefins has so far eluded synthetic chemists.
Vicinal oxidative difunctionalizations (i.e., the creation of two bonds during the same overall transformation such as epoxidation, dihydroxylation, aziridination, amino-hydroxylation and diamination, see Scheme A) of olefins are amongst the most powerful and atom economical maneuvers available for the direct introduction of heteroatoms into simple, unfunctionalized molecules. The resulting difunctional products are obtained in a single step while the molecular complexity is significantly increased (e.g., introducing one or more heteroatoms and stereogenic centers). The resultant products are prized as synthetic building blocks for even larger and structurally more complex molecules such as natural products or active pharmaceutical ingredients. Despite significant advances in this field, many challenges remain that limit the scope and applicability of these difunctionalization reactions, especially in an industrial setting. This is cogently exemplified by the many issues with the direct aminohydroxylation of olefins, a widely used difunctionalization developed by researchers during the 1990s: (1) poor regioselectivity; (2) limited chemoselectivity and substrate scope; (3) use of highly toxic osmium complexes that are difficult to contain due to the comparatively high vapor pressure of osmium derivatives; (4) need for stoichiometric oxidizing agents that pose a fire and explosion hazard, especially when heated; and (5) difficulty in removing the strong electron-withdrawing groups from the N-atom.
In particular, the introduction of unprotected nitrogen in a single step and under mild conditions could result in processes that are faster, more economical, and less wasteful (i.e. greener) than currently used multi-step routes. There exists, therefore, a need in the art for processes to prepare aziridines, including N—H aziridines among others.
